P‐glycoprotein is localized in caveolae in resistant cells and in brain capillaries

MDR1a, 1b, MRP1) mouse fibroblasts showed the same loss of neutral glycosphingolipid (glucosyl ceramide, lactosyl ceramide) but not ganglioside (GM3) synthesis, confirming the proposed role for MDR1 translocase activity. Cryo-immunoelectron microscopy showed MDR1 was predominantly intracellular, largely in rab6-containing Golgi vesicles and Golgi cisternae, the site of glycosphingolipid synthesis. These studies identify MDR1 as the major glucosyl ceramide flippase required for neutral glycosphingolipid anabolism and demonstrate a previously unappreciated dichotomy between neutral and acid glycosphingolipid synthesis.

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“…In some cells (e.g. MDR1-MDCK, SF 539), surface MDR1 expression is remarkably punctate, potentially consistent with a caveolar location (31).…”

Section: Selective Csa Inhibition Of Neutral Glycolipid As Opposed Tomentioning

confidence: 84%

Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

Rosa

Sillence

Ackerley

et al. 2004

Journal of Biological Chemistry

101

107

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“…Interestingly, a tight association has been noted between Caveolin-1 and P-glycoprotein. Indeed, both proteins co-distribute in the same detergent-resistant membrane fractions [47,135,143], and coimmunoprecipitate in brain capillaries, rat brain endothelial, chinese hamster ovary and breast cancer cells [143][144][145]. This interaction appears to be mediated by the presence of a Caveolin-1-binding motif in P-glycoprotein [143].…”

Section: Mechanisms Of Caveolin-1-mediated Drug Resistancementioning

confidence: 94%

The Caveolin-1 Connection to Cell Death and Survival

Quest

Lobos-González²,

Núñez³

et al. 2013

Current Molecular Medicine

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Abstract:Caveolins are a family of membrane proteins required for the formation of small plasma membrane invaginations called caveolae that are implicated in cellular trafficking processes. In addition to this structural role, these scaffolding proteins modulate numerous intracellular signaling pathways; often via direct interaction with specific binding partners. Caveolin-1 is particularly well-studied in this respect and has been attributed a large variety of functions. Thus, Caveolin-1 also represents the best-characterized isoform of this family with respect to its participation in cancer. Rather strikingly, available evidence indicates that Caveolin-1 belongs to a select group of proteins that function, depending on the cellular settings, both as tumor suppressor and promoter of cellular traits commonly associated with enhanced malignant behavior, such as metastasis and multi-drug resistance. The mechanisms underlying such ambiguity in Caveolin-1 function constitute an area of great interest. Here, we will focus on discussing how Caveolin-1 modulates cell death and survival pathways and how this may contribute to a better understanding of the ambiguous role this protein plays in cancer.

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“…P-gp is reported to be localized in caveolae, £ask-shaped invaginations, in which cholesterol and glycosphingolipids are abundant in multidrug-resistant (MDR) cells and in brain capillaries [14,15]. In addition, caveolae containing caveolin-1 reside in the small intestinal brush border membranes [16].…”

Section: Introductionmentioning

confidence: 99%

Involvement of cholesterol in the inhibitory effect of dimethyl‐β‐cyclodextrin on P‐glycoprotein and MRP2 function in Caco‐2 cells

et al. 2003

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We compared the inhibitory e¡ect of various cyclodextrins (CyDs) on P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) function and examined the contribution of cholesterol to the inhibitory e¡ect of 2,on the e¥ux activity of the function in Caco-2 cell monolayers. Of various CyDs, DM-L LCyD signi¢cantly impaired the e¥ux activity of P-gp and MRP2. DM-L L-CyD released P-gp and MRP2 from the monolayers in the apical side's transport bu¡er and decreased the extent of cholesterol as well as P-gp and MRP2 in caveolae of Caco-2 cell monolayers, but not caveolin and £otillin-1. On the other hand, DM-L L-CyD did not change MDR1 and MRP2 mRNA levels. Therefore, these results suggest that the inhibitory e¡ect of DM-L L-CyD on P-gp and MRP2 function, at least in part, could be attributed to the release of these transporters from the apical membranes into the medium as secondary e¡ects through cholesterol-depletion in caveolae after treatment of Caco-2 cell monolayers with DM-L L-CyD. ß

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P‐glycoprotein is localized in caveolae in resistant cells and in brain capillaries

Cited by 142 publications

References 41 publications

Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

The Caveolin-1 Connection to Cell Death and Survival

Involvement of cholesterol in the inhibitory effect of dimethyl‐β‐cyclodextrin on P‐glycoprotein and MRP2 function in Caco‐2 cells

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